More than 1 million small diameter vascular grafts are needed every year for peripheral or coronary bypass surgery. The conduit of choice is an autologous vein or artery, but these are not always available due to pre-existing conditions or previous harvesting. Commercially available biomaterials such as expanded polytetrafluoroethylene (ePTFE) function well as large diameter vascular grafts in the first 5 years but fail dramatically thereafter because of incomplete healing and lack of a protective endothelial layer. Clinical use of ePTFE grafts below 6 mm in diameter is associated with a high rate of narrowing at the proximal anastomosis and ultimately occlusion due to thrombosis and intimal hyperplasia. Thus, new biomaterials capable of supporting a luminal endothelial layer are needed for development of functional small diameter vascular grafts. This study is highly relevant to public health because vascular disease is a very important chapter of health care in the US as well as in third world countries such as South Africa. Long term objective: To develop "off-the-shelf" small diameter grafts that would promote formation of a stable, shear-resistant, endothelial layer to protect the graft from occlusion. Spontaneous luminal coverage with endothelial cells after implantation may occur via two independent mechanisms: 1) Trans-anastomotic endothelialization, whereby endothelial cells migrate laterally across the anastomosis to cover the luminal graft surface and 2) Trans-mural endothelialization, an angiogenic process by which endothelial cells migrate through the thickness of the scaffold to establish a neo-intima. Since trans-anastomotic endothelialization appears to be limited in human implants (as compared to animal models), both mechanisms will be investigated in proposed studies. Working hypothesis: Patent small diameter vascular grafts can be produced by engineering elastin scaffolds that promote endothelialization after implantation. The PI at Clemson University is developing porous elastin-derived vascular grafts (EDVGs) and treatment with penta-galloyl-glucose (PGG) for reversible stabilization. EDVGs were found to be non-thrombogenic in short term implantation studies, exhibited adequate elasticity, burst pressure and compliance, and also degraded slowly, facilitating healing and supporting cell repopulations in subcutaneous studies. Approach: Elastin conduits prepared in the PI's group will be implanted at the University of Cape Town into the rat infrarenal aorta to assess: (i) biocompatibility, patency and ability to support trans- anastomotic endothelialization (Aim 1), and (ii) trans-mural endothelialization in an isolated composite loop model developed by the University of Cape Town whereby the test segment is interposed in between two sections of ePTFE graft material before implantation (Aim 2). After evaluation in the rodent models, EDVGs will be implanted as carotid interposition grafts in pigs, a more clinically relevant large animal model (Aim 3). Demonstration of patency and endothelialization of these elastin-derived scaffolds has great potential for future clinical applications. The proposed research will be performed primarily in the Cardiovascular Research Unit, University of Cape Town, South Africa, in collaboration with Dr. Deon Bezuidenhout, senior lecturer and Professor Peter Zilla, head of department, both acting as co-investigators, as a logical extension of NIH grants R01HL093399 (PI, Dr. Dan Simionescu) and R21EB009835 (PI, Dr. Agneta Simionescu, co-investigator for this proposal), during the period 01/01/2011 to 12/31/2013. PUBLIC HEALTH RELEVANCE: The human body contains an extensive network of vessels that transport blood throughout the body in order to sustain function and life. When these blood vessels become blocked or damaged due to disease or injury, they are surgically replaced or bypassed, preferably by using other natural arteries and veins from the patient's own body. In a large number of cases, however, these preferred substitutes are not suitable or available, and the only current alternatives comprise tubes made of synthetic materials. In many applications these synthetic non-living materials absorb proteins and cells from the blood and become clogged, requiring replacement after 5-10 years. New and improved materials are thus needed for these patients. We are developing alternative natural replacement blood vessels by chemically treating arteries from pigs to render them suitable for use in humans. These tissue engineered blood vessels have inside surfaces which do not induce clogging and have the potential to remodel in the body, and to be repopulated by the patient's own cells, thereby creating new, living arteries. In this study we will implant our new arteries in experimental animals to test their biologic properties. Our new approach will have a global impact in the treatment of vascular disease by providing superior long- term outcomes for thousands of patients.